Table 1.
The summary of recent studies on asymmetric dimethylarginine (ADMA) in acute and chronic liver failure in patients and animal models of HE
| Reference | Subjects | Localization | ADMA | l-Arg | l-Arg/ADMA | DDAH | Findings |
|---|---|---|---|---|---|---|---|
| Bajaj et al. [30] | Patients, (CLF) cirrhosis, TIPS | Plasma | Increased | – | – | – | ADMA levels higher in patients with HE, correlation with cognitive dysfunction |
| Brenner et al. [31] | Patients, (ALF)/sepsis | Plasma | Increased | Increased/decreased | Decreased | – | Measurements of ADMA and l-arg at sepsis onset appeared to be early predictors for survival in septic patients with ALF |
| Mookerjee et al. [32] | Patients, (ALF) (acetaminophen) | Plasma | Increased | – | – | – | Correlation between ADMA levels and proinflammatory cytokines |
| Mookerjee et al. [33] | Patients, (CLF) alcoholic hepatitis | Plasma, liver | Increased in the plasma and liver | – | – | Decreased in the liver (DDAH2) | Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA |
| Lluch et al. [34] | Patients, (CLF) alcoholic cirrhosis | Plasma | Increased | – | Decreased | – | ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis |
| Vizzutti et al. [35] | Patients, (CLF) hepatitis C virus | Plasma | Increased | – | – | – | ADMA correlates with portal pressure |
| Nijveldt et al. [36] | Patients (major hepatectomy) | Plasma | Increased | – | – | – | Increased levels of ADMA occur in the postoperative course after a major hepatic resection |
| Milewski et al. [37] | Rat, TAA (ALF) | Plasma, brain | Increased | – | Decreased | Decreased activity | Histidine decreased brain ADMA level |
| Bekpinar et al. [38] | Rat, TAA (ALF) | Plasma, liver | Increased in the plasma | Decreased in the plasma | Decreased in the plasma | Decreased activity in the liver | Rosiglitazone improved the plasma arginine/ADMA ratio |
| Develi-Is et al. [39] | Rat, TAA (ALF) | Plasma, liver | Increased in the plasma | Decreased in the plasma | – | Decreased activity in the liver | Hemin increased DDAH activity |
| Bal et al. [40] | Rat, (LPS)/d-galactosamine (ALF) | Liver | Increased | Increased | No changes | Decreased activity in the liver | Metformin decreased tissue ADMA level and restored the DDAH activity |
| Ferrigno et al. [41] | Rat, BDLa | Liver | Increased | – | – | No changes | Tissue ADMA increases with a CAT-2-dependent mechanism |
| Sharma et al. [42] | Pig, PCS (ALF) | Plasma | Increased | Decreased | Decreased | – | Relative reduction in l-arginine concentration despite increased de novo production reduction the effect of arginase on NOS by the increase in the levels of ADMA |
| Balasubramaniyan et al. [43] | Rat, BDL (CLF) | Plasma, brain | Increased | No changes in the brain | Decreased in the brain | Decreased in the brain (DDAH1) |
Reduction in ammonia with OP reduces neuroinflammation and restores eNOS activity |
| Huang et al. [44] | Rat, BDL (CLF) BDL + LPSb |
Plasma, liver, kidney | Increased in the plasma | – | Decreased in the plasma | – | In cirrhosis with sepsis, simultaneous lowering of ADMA levels and enhancement of l-arginine levels may be an optimal strategy for the treatment of kidney injury |
| Yang et al. [45] | Rat, BDL (CLF) | Liver | Increased | – | – | Decreased (both isoforms) | Vitamin E suppressed hepatic ADMA and oxidative stress |
| Huang et al. [46] | Rat, BDL (CLF) | Plasma, brain, liver | Increased in the plasma | No changes in the plasma | Decreased in the plasma | No changes in the brain and the liver | Plasma ADMA plays a role in BDL-induced spatial deficit |
| Laleman et al. [47] | Rat, TAA (CLF), BDE (CLF) PPVL (CLF) |
Plasma | Increased in plasma of BDE rats, no changes in the plasma in TAA rats | – | – | – | In rats with biliary cirrhosis, ADMA may mediate decreased NOS activity |
Animal models were ordered according to guidelines accepted by International Society for Hepatic Encephalopathy and nitrogen metabolism [48]
a3-Day cholestasis
b14-Day cirrhosis with superimposed sepsis